Relationship of the Changes in Biogenic Amines to Nitric Oxide and Oxygen Free Radicals During Cerebral Ischemia/Reperfusion

ABSTRACT

Recently oxygen free radicals and nitric oxide (NO) are known to play an important role in neuronal reperfusion injury. This study was aimed to investigate the role of oxygen f ree radicals and NO during cerebral ischemia/reperfusion, using dimethylthiourea (DMTU) and NG-monomethyl-L-arginine (NMMA), an oxygen f ree radical scavenger and a competitive NOS inhibitor respectively. In the in vivo experiment, the ischemia/reperfusion-induced changes of cerebral biogenic amines were examined in Mongolian gerbil (Meriones unguiculatus) pre-treated with NMMA and/or DMTU. To induce cerebral ischemia/reperfusion, bilateral common carotid arteries were clamped for 10 minutes and then released for 15 minutes. The biogenic amines were measured by using HPLC-ECD(High Performance Liquid Chromatography-Electrochemical detection). To confirm the results from the in vivo experiments, the effect of NMMA and/or DMTU on [3H]dopamine release from striatal slices exposed to hypoxia was investigated. The results are as follows; 1) Ischemia/reperfusion increased the ratio of DOPAC/dopamine and HVA/dopamine as well as the concentrations of DOPAC and HVA, which were evident only in corpus striatum. 2) NMMA attenuated the ischemia/reperfusion-induced increase in the ratio of DOPAC/dopamine in corpus striatum. However, the change of DOPAC or HVA was minimal. 3) DMTU attenuated the ischemia/reperfusion-induced increase of DOPAC and HVA, and the ratio ofDOPAC / dopa- mine and HVA/dopamine in corpus striatum. 4) Simultaneous pre-treatment with NMMA and DMTU attenuated the ischemia/reperfusion-induced increase of DOPAC and HVA, and the ratio Of DOPAC/dopamine and HVA/dopamine in corpus striatum. The extent of attenuation was greater than the single treatment group with NMMA or DMTU. 5) Exposure to hypoxia markedly increased the release of [3H]dopamine in the striatal slices. 6) The administration of either NMMA or DMTU attenuated the increase of [3H]dopamine release induced by hypoxia in the striatal slices. 7) The administration of both NMMA or DMTU markedly attenuated the increase of [3H]dopamine release induced by hypoxia to the extent of the control in the striatal slices. These results suggest that oxygen free radicals play an important role in cerebral ischemia/reperfusion injury, for which NO seems to be responsible.